Benzofuran-2-carboxylic acids

ABSTRACT

Compounds of the class of 4-(2-methylene-alkoyl-2-carboxylic acids and the pharmaceutically acceptable salts thereof with bases have diuretic and saluretic effects in mammals; pharmaceutical compositions comprising said compounds and a pharmaceutical carrier, and methods of producing a diuretic and saluretic effect in mammals are provided; a typical embodiment is 6-methyl-4-(2-methylene-butyryl)-benzofuran-2-carboxylic acid.

United States Patent 5 [72] inventors JlnoeZergenyi App]. No. FiledPatented Assignee Priority Riehen; Ernst Habicht, Oberwil, both ofSwitzerland July 7, 1969 Dec. 14, 1971 Geigy Chemical CorporationArdsley, N.Y.

July 22, 1968 Switzerland BENZOFURAN-Z-CARBOXYLIC ACIDS 4 Claims, NoDrawings U.S. Cl 260/3462, 424/255 Int. Cl

[50] Field of Search 260/3462 R References Cited OTHER REFERENCES Gilmanet al. Chem. Abstr. (1940) Vol. 34 pp. 2366 Primary Examiner-Alex Maze]Assistant Examiner-Bernard l. Dentz Attorneys-Karl F. .lorda and BruceM. Collins BENZOFURAN-Z-CARBOXYLIC ACIDS DETAILED DISCLOSURE wherein Ris alkyl having at most three carbon atoms; and

Z and Z independently of each other are hydrogen,

methyl, ethyl, methoxy or ethoxy; and

the pharmaceutically acceptable salts thereof with bases.

A preferred subclass are compounds of formula I wherein R is ethyl, andthe pharmaceutically acceptable salts thereof with bases.

Preferred members are 6-methyl-4-(Z-methyIene-butyryl)-benzofuran-2-carboxylic acid, and

6,7-dimethyl-4-( Z-methylene-butyryl )-benzofuran-2-carboxylic acid, andthe pharmaceutically acceptable salts thereof with bases.

The invention pertains also to pharmaceutical compositions comprising acompound of formula I and/or a pharmaceutically acceptable salt thereofwith bases and a pharmaceutical carrier therefor.

Furthermore, the invention pertains to a method of producing diuresisand saluresis in mammals which method comprises administering to saidmammal an effective amount of a compound of formula I or of apharmaceutically acceptable salt thereof with a base.

In the benzofuran-Z-carboxylic acids of formula I, Z, occupies the 5- or6-position and Z the 6- or 7-position. As lower alkyl having at mostthree carbon atoms, R is methyl, ethyl, propyl or isopropyl.

Compounds of formula 1 are produced, according to the invention, bydecomposing a compound of formula II Z2 (II) wherein R, Z and Z have themeaning given under formula I, and Am is the radical of a secondaryorganic base, with the thereby-occurring splitting off of an amine offormula III HAm ([11) wherein Am has the meaning given under formula lland, optionally,

converting the reaction product into a salt with an inorganic or organicbase.

A compound of formula ll is preferably decomposed by heating in thepresence of a weak base in a solvent containing hydroxyl groups.Suitable weak bases are, eg sodium acetate or sodium hydrogen carbonate;they are preferably used in glacial acetic acid or water.

As starting materials of formula I], such materials are used forexample, which correspond to the more restricted formula [la wherein Amis lower dialkylamino such as dimethylamino or diethylamino,l-pyrrolidinyl, piperidino, hexahydro-IH- l-a'zepinyl or morpholino andR, Z, and A have the meanings given under formula l.

Suitable starting materials of. formulas ll and lla are e.g.

compounds whose substituents R, Z, and Z, conform to the groups listedunder formula I. These starting materials can for example, be producedfrom carboxylic acids of formula IV COOH wherein Z, and Z, have themeanings given under formula I.

These (V) are condensed according to the Friedel-Crafts reaction, usingaluminum chloride in nitrobenzene, with carboxylic acid chlorides offormula V,

RCh,--COCl wherein R has the meaning given under formula I, to give thecorresponding 4-alkanoyl derivatives. Such alkanoyl derivatives are,e.g. the 4-acetyl-, 4-propionyl-, 4-butyryl-, 4- valerylor 4-isovalerylderivatives of the benzofuran-Z- carboxylic acid, which are optionallysubstituted by the substituents 2. and/or Z, in 5- or 6-position or 6-or 7- position. The stated 4-alkanoyl derivatives are subsequentlyconverted, with the aid of formaldehyde or paraformaldehyde and asecondary organic base, into the corresponding Mannich compounds offormulas ll or lla.

Suitable carboxylic acids of formulalV are, e.g. compounds havingradicals Z, and Z which conform to the groups listed under formula I.Such like compounds are described in he literature, e.g. thebenzofuran-2-carboxylic acid [cp. R. Fitting et al. Ann. Chem. 216, 162(1883)],the S-methylbenzofuran-Z-carboxylic acid [cp. R. Andrisano andG. Pappalario, Gazz. chim.ital. 83, 108 (1953)], the6-methylbenzofuran-Z-carboxylic, acid [cp. K. von Auwers, Ann. Chem.408, 255 (1915)], the 7-methoxy-benzofuran-2-carboxylic acid [cp. R.Andrisano et al., Boll.sci.fac.chim.ind. I4, 96 (1956)] and the5-methoxy-benzofuran-2-carboxylic acid [cp. S. Tanaka J.Am.Chem.Soc.73,872 (I! )1. Other compounds of this type can be produced analogously.

For the preparation of pharmaceutically acceptable salts can be usedinorganic and organic bases, such as alkali. or alkaline earthhydroxides, carbonates or bicarbonates. Suitable are thus e.g. sodium,potassium, magnesium and calcium hydroxides, carbonates or bicarbonates,as well as triethanolamine and choline. Such salts are produced via conventional methods, e.g. by mixing a compound of formula I with theequivalent amount of the desired base in a suitable solvent such aswater, mixture of water with an organic solvent or in organic solventsalone such as methanol, ethanol, or propanol and isolating the saltsformed in a conventional manner.

The compounds of the invention have been found to have valuablepharmacological properties. In particular, they have a diuretic andsimultaneously saluretic action in combination with a low order oftoxicity. The excretion of potassium in proportion to sodium is veryfavorable. These properties characterize the compounds as being suitablefor the treatment of disturbances caused by insufficient excretion ofurine and electrolytes, especially of sodium chloride. Such disturbancesare the cause of edema and hypertension.

The diuretic and saluretic efiects of the compounds of the invention areillustratively demonstrated in experimental animals. Thus it can beshown by conventional pharmacological experiments that6-methyl-4-(2-methylene-butyryl)- benzofuran-Z-carboxylic acid and6,7-dimethyl-4-(2- methylene-butyryl)-benzofuran-2-carboxylic acid onperoral administration of about 5 mgJkg. to dogs significantly in-'crease the excretion of urine and simultaneously of sodium chloride.

The carboxylic acids of formula I, and the pharmaceutically acceptablesalts thereof, are preferably administered orally. The doses depend onthe species, the age and weight of the subject under treatment as wellas on the particular condition to be treated. In general, the dailydosages vary between 1 and 20 mg./ kg. for mammals. Suitable dosageunits such as drag es or tablets, preferably contain as active substance25 to 500 mg. of a benzofuran-Z-carboxylic acid of formula I, or of apharmaceutically acceptable salt thereof. The proportion of activesubstance is preferably 20 to 80 percent in the stated dosage units.Dosage units for oral administration are produced by combining theactive substance, e.g. with solid, pulverulent carriers such as lactose,saccharose, sorbitol, mannitol; starches such as potato starch, maizestarch of amylopectin, also laminaria powder or citrus pulp powder;cellulose derivatives or gelatine, optionally with the addition oflubricants such as magnesium or calcium stearate or polyethyleneglycols, to form tablets or drage cores. The

latter are coated, e.g. with concentrated sugar solutions which can alsocontain e.g. gum arabic, talcum and/or titanium dioxide, or with alacquer dissolved in easily volatile organic solvents or mixtures ofsolvents. Dyestuffs can be added to these coatings, e.g. to distinguishbetween varying dosages of activ substance. I

The following examples further illustrate the production of compounds offormula] and of hitherto-undescribed intermediate products as well asthe production of pharmaceutical compositions, but they are by no meansthe sole methods of producing same. Temperatures are given in degreescentigrade.

EXAMPLE 1 a. 2.0 g. of 6-methyl-4-butyryl-benzofuran-2-carboxylic acidwith 0.41 g. of paraformaldehyde and 0.82 g. of dimethylaminehydrochloride are slurried in 20 ml. of dioxane and the whole isrefluxed for 6 hours while stirring. The dioxane is then distilled offunder normal pressure. To the residue, i.e. the crude6-methyl-4-[2-(dimethylaminomethyl)-butyryl]- benzofuran-Z-carboxylicacid hydrochloride, are added 20 ml. of glacial acetic acid and 2.0 g.of sodium acetate and the mixture is refluxed for 2 hours. The glacialacetic acid is then evaporated ofi in vacuo, the residue taken up in 50ml. of water and the mixture acidified with concentrated hydrochloricacid to obtain pH 2-3. The acid-aqueous suspension is stirred for halfan hour at room temperature, the precipitated crystals are then filteredwith suction, dried in vacuo at 60 and recrystallized from benzene/ethylacetate. The obtained6-methyl-4-(Z-methyIene-butyryl)-benzofuran-2-carboxylic acid melts atl68l69.

The 6-methyl-4-butyryl-benzofuran-2-carboxylic acid, used as startingmaterial, is produced as follows:

b. 10.0 g. of 6-methyl-beniofuran-Z-carboxylic acid [cp. K. von Auwers,Ann.Chem. 408, 255 (1915)] are suspended in 30 ml. of nitrobenzene. 28.0g. of aluminum chloride are added in portions to the suspension, whilecooling with ice, so that a reaction temperature of is maintained. 9.0g. of butyryl chloride are then added dropwise within 30 minutes at thesame temperature. The mixture is subsequently stirred for 24 hours at 25then poured onto 300 g. of ice and 50 ml. of

concentrated hydrochloric acid and the acid-aqueous suspension extractedtwice using 300 ml. of ether each time. The combined ether solutions arewashed with water and extracted twice using 100 ml. of saturated sodiumhydrogen carbonate solution each time. The sodium hydrogen carbonateextract is adjusted to pH 2-3 with concentrated hydrochloric acid andthe obtained suspension stirred for 1 hour at room temperature. Theprecipitated crystals are filtered with suction, washed with water anddissolved in ethyl acetate. The ethyl acetate solution is dried withanhydrous magnesium sulfate and concentrated by evaporation in vacuo, Bymeans of fractional recrystallization of the residue from ethylacetate/dioxane is obtained, in addition to the6-methyl-5-butyryl-benzofuran-Z-carboxylic acid, the6-methyl-4-butyryl-benzofuran-2- carboxylic acid, m.p. 21 l-2l2 (fromethyl acetate/dioxane).

EXAMPLE 2 a. From 2.5 g. of S-methyl-4-butyryl benzofuran-Z-carboxylicacid with 0.6 g. of paraformaldehyde and L2 g. of dimethylaminehydrochloride is obtained, analogously to example l(a), the crude 5-methyl-4-[2-(dimethylaminomethyl)- butyryll-benzofuran-Zcarboxylic acidhydrochloride, which is converted with 3.0 g. of sodium acetate and 30ml. of glacial acetic acid into the 5-methyl-4-(Z-methyIene-butyryl)-benzofuran-Z-carboxylic acid, m.p. l65l66 (from ethyl acetate).

The starting compound, i.e. the5-methyl-4-butyrylbenzofuran-Z-carboxylic acid, is produced as follows:

b. 26.3 g. of 5-methyl-benzofuran-2-carboxylic acid [cp. R. Andrisanoand G. Pappalario, Gazz. chim.ital. 83, 108 (1953 )]are suspended in 100ml. of nitrobenzene and cooled to 0. To this suspension are added 70.0g. of pulverized aluminum chloride in portions, so that the reactiontemperature does not exceed 10. 20.0 g. of butyryl chloride are thenadded dropwise at the same temperature. The reaction mixture is stirredfor 64 hours at room temperature and then for 6 hours 60. The reactionmixture is then poured onto a mixture of 400 g. of ice and 100 ml. ofconcentrated hydrochloric acid. The acid-aqueous'suspension is extractedtwice using 250 ml. of ether each time, the ether extract washed with200 ml. of water and then extracted twice with 100 ml. of concentratedsodium hydrogen carbonate solution each time. The combined sodiumhydrogen carbonate solutions are adjusted with concentrated hydrochloricacid to pH 2-3. The obtained suspension is then extracted twice using200 ml. of ether each time. After washing with water, the ether phase isdried with sodium sulfate and concentrated by evaporation. The residuecan be separated into two fractions by elution chromatography on acolumn of 500 g. of silica gel with the eluting agentbenzene/ether/glacial acetic acid (95:4:1). THe first fraction containsthe 4-butyryl'-5-methyl-benzofuran-Z-carboxylic acid, m.p. l43-146 (fromethyl acetate).

EXAMPLE 3 From 3.0 g. of 7-methoxy-4-butyryl-benzofuran-Z-carboxylicacid with 2.6 g. of paraformaldehyde and 5.3 g. of dimethylaminehydrochloride in ml. of dioxane is obtained, analogously to example1(a), the crude 7-methoxy-4-[2- (dimethylaminomethyl)-butyryl]-benzofuran-2-carboxylic EXAMPLE 4 a. From. 10.0 g. of6,7-dimethyl-4-butyryl-benzofuran-Z-carboxylic acid with 1.64 g. ofparaforrnaldehyde and 3.3 g. of dimethylamine hydrochloride is obtained,analogously to example 1(a), the crude 6,7-dimethyl-4-[2-(dimethylaminomethyl)-butyryll-benzofuran-Z-carboxylic acidhydrochloride, which, is converted with 10.0 g. of sodium acetate and100 ml. of glacial acetic acid into the 6,7- dimethy1-4-(Z-methylene-butyryl )-benzofuran-2-carboxylic acid, m.p. 200-202 frombenzene/ethyl acetate).

The 6,7-dimethyl-4-butyrl benzofuran-2-carboxylic acid, used as startingmaterial, is produced as follow:

b. 45.0 c. of 2,3-dimethylphenol and 50.0 g. of malic acid arepulverized and well mixed together. One hundred milliliters ofconcentrated sulfuric acid are added to the mixture and the latter,while stirring, is slowly heated so that the reaction temperature is 130after 30 minutes. The solution is maintained for a further 30 minutes atthis temperature, then poured onto 1 kg. of ice and the obtainedsuspensionis stirred for 30 minutes. The precipitated crystals arefiltered with suction and recrystallized from ethanol. 7,8-dimethylcoumarin is obtained, m.p. l28-130.

c. 34.8 g. of the 7,8-dimethyl coumarin, obtained under (b), aredissolved in 60 ml. of chloroform. To this solution is added dropwise,while stirring andwith occasional cooling with ice, a solution of 32.5g. of bromine in 20 ml. of chloroform, so that the reaction temperaturedoes not exceed 2025. The mixture is stirred for a further 20 minutes atroom temperature and, subsequently, the chloroform is completelyevaporated ofi in vacuo. The residue is added in portions to asuspension of 90.0 g. of potassium hydroxide in 300 ml. of ethanol andthe reaction temperature is maintained between 30 and 40 by ice cooling.The mixture is then stirred for 30 minutes at 40 and for 30 minutes at80 and then poured onto 2 liters of ice water. The aqueous alkalinesolution is washed twice using 400 ml. of ether each time and adjustedto pH 23 with concentrated hydrochloric acid. The obtained suspension isstirred for half an hour at room temperature. The precipitated crystalsare filtered with suction and recrystallized from ethanol. The6,7-diemthyl-benzofuran-2-carboxylic acid, m.p. 237239 is obtained.

d. From 23.0 g. of the carboxylic acid, obtained under (c), with 20.0 g.of butyryl chloride and 70. g. of aluminum chloride in 80 ml. ofnitrobenzene is obtained, analogously to example l(b), the6,7-dimethyl-4-butyryl-benzofuran-Z-carboxylic acid, m.p. 207208 (fromethanol).

EXAMPLE 5 a. From 5.0 g. of 6-ethyl-4-butyryl-benzofuran-Z-carboxylicacid with L09 g. of paraformaldehyde and 2.10 g. of dimethylaminehydrochloride is obtained, analogously to example l(a), the crude6-ethyl- 4-[2-(dimethylaminomethyl)- butyryl]-benzofuran-2-carboxylicacid hydrochloride, which is converted with 5.0 g. of sodium acetate and50 ml. of glacial acetic acid into the6ethyl-4-(Z-methyIene-butyryl)-benzofuran-Z-carboxylic acid, m.p.l45-l46 (from benzene/ethyl acetate).

The 6-ethyl-4-butyryl-benzofuran-2-carboxylic acid, used as startingmaterial, is produced as follows:

b. 50.0 g. of m-ethylphenol, 55.0 g. of malic acid and 100 ml. ofconcentrated sulfuric acid are slowly heated, while stirring, to 130 andthen further stirred for minutes at this temperature. The reactionmixture is then poured onto 2 kg. of ice and extracted with 500 ml. ofether. The ether extract is washed with 200 ml. of water and with 200ml. of concentrated aqueous sodium hydrogen carbonate solution, driedover magnesium sulfate and concentrated by evaporation. The residue,i.e. the crude 7-ethyl coumarin, is used as crude product.

c. 30.4 g. of 7-ethyl coumarin are dissolved in 40 ml. chloroform and tothe solution are added dropwise, while stirring, 29.0 g. of bromine in20 ml. of chloroform. The temperature of the reaction mixture ismaintained between 20 and 25 by occasional cooling with an ice bath. Thereaction mixture is subsequently further stirred for 20 minutes at roomtemperature and concentrated by evaporation at 50 in the water-jetvacuum. The residue is added in portions to a solution of 80.0 g. ofpotassium hydroxide in 160 ml. of ethanol, which is heated to 30, andthe reaction temperature is maintained at 304O by cooling. The reactionmixture is subsequently stirred for 30 minutes at room temperature andfor 30 minutes at and then poured onto 1 liter of ice water. The aqueousalkaline solution is washed twice with 300 ml. of ether each time,acidified with concentrated hydrochloric acid to obtain pH 2-3 and theprecipitated crude product is filtered with suction. The crude productis recrystallized from ethanol and dried in vacuo at 80, after which theobtained 6-ethylbenzofuran-Z-carboxylic acid melts at l52l 54.

d. From -ethyl-benzofuran-Z-carboxylic acid with butyric acid chlorideand aluminum chloride in nitrobenzene is obtained, analogously toexample l(b), the 6-ethyl-4-butyrylbenzofuran-Z-carboxylic acid, m.p.l97-l99 (from benzene/ethyl acetate), in addition to the6-ethyl-5-butyrylbenzofuran-"carboxylic acid, m.p. 152l53, from whichthe former is separated by fractional recrystallization from ethylacetate.

EXAMPLE 6 From 6.5 g. of 5-methoxy-4-butyryl-benzofuran-Z-carboxylicacid with 1.0 g. of paraformaldehyde and 2.5 g. of dimethylaminehydrochloride is obtained, analogously to example l (a), the crude5-methoxy-4-[ 2- (dimethylaminomethyl)-butyryl]-benzofuran-2-carboxylicacid hydrochloride, which is converted with 5.0 g. of sodium acetate in50 ml. of glacial acetic acid into the 5-methoxy-4-(2 EXAMPLE 7 1.8 g.of 6-methyl-4-(3-methylbutyryl)-benzofuran-2-carboxylic acid with 0.7g.of paraformaldehyde and 2.2 g. of dimethylamine hydrochloride areslurried in 10 ml. of methanol. The methanol is then distilled off undernormal pressure and the reaction mixture is subsequently heated for 8hours to The obtained melt, which consists of the crude 6-methyl-4-(3-methyl-2-dimethylaminomethylbutyryl)- benzofuran-Z-carboxylic acidhydrochloride, is allowed to cool. 3.0 g. of anhydrous sodium acetateand 30 ml. of glacial acetic acid are then added and the obtainedsolution is refluxed, while stirring, for 2 hours. The glacial aceticacid is then distilled off, to the residue are added 50 ml. of water andthe mixture is adjusted to 3 3 with concentrated hydrochloric acid. Themixture is further stirred to obtain complete crystallization, thecrystals are filtered off with suction, washed with 50 ml. of water anddried in vacuo. The 6-methyl-4 -(2-methylene-3-methylbutyryl)-benzofuran-2-carboxylic acid, recrystallizedfrom benzene, melts at 155l56.

The 6-methyl-4-( 3-methylbutyryl,l-benzofuran-2-carboxylic acid, used asstarting material is produced analogously to example l(b) from6-methyl-benzofuran-2-carboxylic acid [cp. K. von Auwers, Ann.Chem. 408,255 (1915)] with isovaleryl chloride and aluminum chloride innitrobenzene. The crude product contains, in addition to the6-methyl-4-(3-methylbutyryl)-benzofuran-2-carboxylic acid, m.p. l92-193,the 6- methyl-5-( 3-methylbutyryl )-benzofuran-2-carboxylic acid, whichare separated from each other by fractional crystallization from ethylacetate.

EXAMPLE 8 dimethylamine hydrochloride is obtained. analogously toexample 1(a) the crude6-methyl-4-(Z-dimethylaminomethylpropionyl)-benzofuran'2-carboxylic acidhydrochloride, which is converted with sodium acetate in glacial aceticacid into the 6-methy1-4-(Z-methyIene-propionyl)-benzofuran-2-carboxylic acid, m.p. l82-1 83 (from benzene).

The 6-methyl-4-propionyl-benzofuran-2-carboxylic acid is produced,analogously to example 1(b) from 6-methylbenzofuran-Z-carboxylic acid[cp. K. von Auwers, Ann.Chem. 408, 255 (1915)] with propionyl chlorideand aluminum chloride in nitrobenzene. By means of fractionalcrystallization from dioxane/ethyl acetate is obtained the 6-methyl-4-propionyl-benzofuran-Z-carboxylic acid, which melts at EXAMPLE 9 From1.0 g. of 6-methyl-4-valeryl-benzofuran-Z-carboxylic acid with 0.3 g. ofparaformaldehyde and 0.8 g. of dimethylamine hydrochloride is obtained,analogously to example 1(a), the crude6-methyl-4-(Z-dimethylaminomethylvaleryl)-benzofuran 2carboxylic acidhydrochloride, which is converted with sodium acetate in glacial aceticacid into the 6- EXAMPLE 10 One thousand grams of 6-methyl-4-(Z-methylene-butyryU- benzofuran-Z-carboxylic acid are mixed with 550 g.of lactose and 292 g. of potato starch. The mixture is moistened with anaqueous solution of 8 g. of gelatine and granulated through a sieve.After drying, 60 g. of potato starch, 60 g. of talcum, 10 g. ofmagnesium stearate and 20 g. of colloidal silicon dioxide are mixed inand the mixture is pressed into 10,000 tablets. each weighing 200 mg.and each containing mg. of active substance. Optionally, the tablets canbe provided with grooves for more accurate adjustment of the dosageamount.

EXAMPLE 1| A granulate is produced from 1,000 g. of 6,7-dimethyl-4-( 2-methylene-butyryl)-benzofuran-2-carboxylic acid. 379 g. of lactose andthe aqueous solution of 6 g. of gelatine. After drying, the granulate ismixed with 10 g. of colloidal silicon dioxide, 40 g. of talcum, 60 g. ofpotato starch and 5 g. of magnesium stearate and the obtained mixture ispressed into 10,000 drage cores. These are subsequently coated with aconcentrated syrup made from 533.5 g. of crystallized saccharose, 20 g.of shellac, 75 g. of gum arabic, 250 g. of talcum, 20 g. of colloidalsilicon dioxide and 1.5 g. of dyestutl, and dried. The obtained dra geseach weigh 240 mg. and each contain 100 mg.

of active substance.

What is claimed is: 1. A compound of the formula

2. A compound according to claim 1, wherein R is ethyl.
 3. A compoundaccording to claim 1, which is6-methyl-4-(2-methylene-butyryl)-benzofuran-2-carboxylic acid.
 4. Acompound according to claim 1, which is6,7-dimethyl-4-(2-methylene-butyryl)-benzofuran-2-carboxylic acid.